Skip to main content
Log in

Glucagon-Like Peptide 1 (GLP-1) Can Reverse AMP-Activated Protein Kinase (AMPK) and S6 Kinase (P70S6K) Activities Induced by Fluctuations in Glucose Levels in Hypothalamic Areas Involved in Feeding Behaviour

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The anorexigenic peptide, glucagon-like peptide-1 (GLP-1), reduces glucose metabolism in the human hypothalamus and brain stem. The brain activity of metabolic sensors such as AMP-activated protein kinase (AMPK) responds to changes in glucose levels. The mammalian target of rapamycin (mTOR) and its downstream target, p70S6 kinase (p70S6K), integrate nutrient and hormonal signals. The hypothalamic mTOR/p70S6K pathway has been implicated in the control of feeding and the regulation of energy balances. Therefore, we investigated the coordinated effects of glucose and GLP-1 on the expression and activity of AMPK and p70S6K in the areas involved in the control of feeding. The effect of GLP-1 on the expression and activities of AMPK and p70S6K was studied in hypothalamic slice explants exposed to low- and high-glucose concentrations by quantitative real-time RT-PCR and by the quantification of active-phosphorylated protein levels by immunoblot. In vivo, the effects of exendin-4 on hypothalamic AMPK and p70S6K activation were analysed in male obese Zucker and lean controls 1 h after exendin-4 injection to rats fasted for 48 h or after re-feeding for 2–4 h. High-glucose levels decreased the expression of Ampk in the lateral hypothalamus and treatment with GLP-1 reversed this effect. GLP-1 treatment inhibited the activities of AMPK and p70S6K when the activation of these protein kinases was maximum in both the ventromedial and lateral hypothalamic areas. Furthermore, in vivo s.c. administration of exendin-4 modulated AMPK and p70S6K activities in those areas, in both fasted and re-fed obese Zucker and lean control rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Hardie DG, Carling D, Carlson M (1998) The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Annu Rev Biochem 67:821–855

    Article  PubMed  CAS  Google Scholar 

  2. Rutter GA, Da Silva XG, Leclerc I (2003) Roles of 5′-AMP-activated protein kinase (AMPK) in mammalian glucose homoeostasis. Biochem J 375(Pt 1):1–16

    Article  PubMed  CAS  Google Scholar 

  3. Hardie DG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8(10):774–785

    Article  PubMed  CAS  Google Scholar 

  4. Jorgensen SB, Viollet B, Andreelli F, Frosig C, Birk JB, Schjerling P, Vaulont S, Richter EA, Wojtaszewski JF (2004) Knockout of the alpha2 but not alpha1 5′-AMP-activated protein kinase isoform abolishes 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranosidebut not contraction-induced glucose uptake in skeletal muscle. J Biol Chem 279(2):1070–1079

    Article  PubMed  CAS  Google Scholar 

  5. Viollet B, Andreelli F, Jorgensen SB, Perrin C, Geloen A, Flamez D, Mu J, Lenzner C, Baud O, Bennoun M, Gomas E, Nicolas G, Wojtaszewski JF, Kahn A, Carling D, Schuit FC, Birnbaum MJ, Richter EA, Burcelin R, Vaulont S (2003) The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity. J Clin Invest 111(1):91–98

    PubMed  CAS  Google Scholar 

  6. Viollet B, Athea Y, Mounier R, Guigas B, Zarrinpashneh E, Horman S, Lantier L, Hebrard S, Devin-Leclerc J, Beauloye C, Foretz M, Andreelli F, Ventura-Clapier R, Bertrand L (2009) AMPK: lessons from transgenic and knockout animals. Front Biosci 14:19–44

    Article  PubMed  CAS  Google Scholar 

  7. Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, Stuck BJ, Kahn BB (2004) AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428(6982):569–574

    Article  PubMed  CAS  Google Scholar 

  8. Kim MS, Park JY, Namkoong C, Jang PG, Ryu JW, Song HS, Yun JY, Namgoong IS, Ha J, Park IS, Lee IK, Viollet B, Youn JH, Lee HK, Lee KU (2004) Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med 10(7):727–733

    Article  PubMed  CAS  Google Scholar 

  9. Lim CT, Kola B, Korbonits M (2010) AMPK as a mediator of hormonal signalling. J Mol Endocrinol 44(2):87–97

    Article  PubMed  CAS  Google Scholar 

  10. Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ (2006) Hypothalamic mTOR signaling regulates food intake. Science 312(5775):927–930

    Article  PubMed  CAS  Google Scholar 

  11. Vodenik B, Rovira J, Campistol JM (2009) Mammalian target of rapamycin and diabetes: what does the current evidence tell us? Transplant Proc 41(6 Suppl):S31–S38

    Article  PubMed  CAS  Google Scholar 

  12. Alvarez E, Roncero I, Chowen JA, Thorens B, Blazquez E (1996) Expression of the glucagon-like peptide-1 receptor gene in rat brain. J Neurochem 66(3):920–927

    Article  PubMed  CAS  Google Scholar 

  13. Blazquez E, Alvarez E, Navarro M, Roncero I, Rodriguez-Fonseca F, Chowen JA, Zueco JA (1998) Glucagon-like peptide-1 (7–36) amide as a novel neuropeptide. Mol Neurobiol 18(2):157–173

    Article  PubMed  CAS  Google Scholar 

  14. Navarro M, Rodriquez de Fonseca F, Alvarez E, Chowen JA, Zueco JA, Gomez R, Eng J, Blazquez E (1996) Colocalization of glucagon-like peptide-1 (GLP-1) receptors, glucose transporter GLUT-2, and glucokinase mRNAs in rat hypothalamic cells: evidence for a role of GLP-1 receptor agonists as an inhibitory signal for food and water intake. J Neurochem 67(5):1982–1991

    Article  PubMed  CAS  Google Scholar 

  15. Rodriguez de Fonseca F, Navarro M, Alvarez E, Roncero I, Chowen JA, Maestre O, Gomez R, Munoz RM, Eng J, Blazquez E (2000) Peripheral versus central effects of glucagon-like peptide-1 receptor agonists on satiety and body weight loss in Zucker obese rats. Metabolism 49(6):709–717

    Article  Google Scholar 

  16. Turton MD, O’Shea D, Gunn I, Beak SA, Edwards CM, Meeran K, Choi SJ, Taylor GM, Heath MM, Lambert PD, Wilding JP, Smith DM, Ghatei MA, Herbert J, Bloom SR (1996) A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379(6560):69–72

    Article  PubMed  CAS  Google Scholar 

  17. Alvarez E, Martinez MD, Roncero I, Chowen JA, Garcia-Cuartero B, Gispert JD, Sanz C, Vazquez P, Maldonado A, de Caceres J, Desco M, Pozo MA, Blazquez E (2005) The expression of GLP-1 receptor mRNA and protein allows the effect of GLP-1 on glucose metabolism in the human hypothalamus and brainstem. J Neurochem 92(4):798–806

    Article  PubMed  CAS  Google Scholar 

  18. Alvarez E, Roncero I, Chowen JA, Vazquez P, Blazquez E (2002) Evidence that glucokinase regulatory protein is expressed and interacts with glucokinase in rat brain. J Neurochem 80(1):45–53

    Article  PubMed  CAS  Google Scholar 

  19. Roncero I, Alvarez E, Chowen JA, Sanz C, Rabano A, Vazquez P, Blazquez E (2004) Expression of glucose transporter isoform GLUT-2 and glucokinase genes in human brain. J Neurochem 88(5):1203–1210

    Article  PubMed  CAS  Google Scholar 

  20. Roncero I, Alvarez E, Vazquez P, Blazquez E (2000) Functional glucokinase isoforms are expressed in rat brain. J Neurochem 74(5):1848–1857

    Article  PubMed  CAS  Google Scholar 

  21. Mountjoy PD, Bailey SJ, Rutter GA (2007) Inhibition by glucose or leptin of hypothalamic neurons expressing neuropeptide Y requires changes in AMP-activated protein kinase activity. Diabetologia 50(1):168–177

    Article  PubMed  CAS  Google Scholar 

  22. Claret M, Smith MA, Batterham RL, Selman C, Choudhury AI, Fryer LG, Clements M, Al-Qassab H, Heffron H, Xu AW, Speakman JR, Barsh GS, Viollet B, Vaulont S, Ashford ML, Carling D, Withers DJ (2007) AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J Clin Invest 117(8):2325–2336

    Article  PubMed  CAS  Google Scholar 

  23. Niswender K (2010) Diabetes and obesity: therapeutic targeting and risk reduction—a complex interplay. Diabetes Obes Metab 12(4):267–287

    Article  PubMed  Google Scholar 

  24. Blonde L, Klein EJ, Han J, Zhang B, Mac SM, Poon TH, Taylor KL, Trautmann ME, Kim DD, Kendall DM (2006) Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab 8(4):436–447

    Article  PubMed  CAS  Google Scholar 

  25. Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, Zychma M, Blonde L (2009) Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 374(9683):39–47

    Article  PubMed  CAS  Google Scholar 

  26. Montanya E, Sesti G (2009) A review of efficacy and safety data regarding the use of liraglutide, a once-daily human glucagon-like peptide 1 analogue, in the treatment of type 2 diabetes mellitus. Clin Ther 31(11):2472–2488

    Article  PubMed  CAS  Google Scholar 

  27. Sanz C, Roncero I, Vazquez P, Navas MA, Blazquez E (2007) Effects of glucose and insulin on glucokinase activity in rat hypothalamus. J Endocrinol 193(2):259–267

    Article  PubMed  CAS  Google Scholar 

  28. Sanz C, Vazquez P, Navas MA, Alvarez E, Blazquez E (2008) Leptin but not neuropeptide Y up-regulated glucagon-like peptide 1 receptor expression in GT1–7 cells and rat hypothalamic slices. Metabolism 57(1):40–48

    Article  PubMed  CAS  Google Scholar 

  29. Mellon PL, Windle JJ, Goldsmith PC, Padula CA, Roberts JL, Weiner RI (1990) Immortalization of hypothalamic GnRH neurons by genetically targeted tumorigenesis. Neuron 5(1):1–10

    Article  PubMed  CAS  Google Scholar 

  30. Paxinos G, Watson C (2004) The rat brain in stereotaxic coordinates. Elsevier, New York

    Google Scholar 

  31. Hardie DG, Hawley SA, Scott JW (2006) AMP-activated protein kinase—development of the energy sensor concept. J Physiol 574(Pt 1):7–15

    Article  PubMed  CAS  Google Scholar 

  32. Mountjoy PD, Rutter GA (2007) Glucose sensing by hypothalamic neurones and pancreatic islet cells: AMPle evidence for common mechanisms? Exp Physiol 92(2):311–319

    Article  PubMed  CAS  Google Scholar 

  33. Solomon A, De Fanti BA, Martinez JA (2006) Peripheral ghrelin participates in the glucostatic signaling mediated by the ventromedial and lateral hypothalamus neurons. Peptides 27(7):1607–1615

    Article  PubMed  CAS  Google Scholar 

  34. McCrimmon RJ, Shaw M, Fan X, Cheng H, Ding Y, Vella MC, Zhou L, McNay EC, Sherwin RS (2008) Key role for AMP-activated protein kinase in the ventromedial hypothalamus in regulating counterregulatory hormone responses to acute hypoglycemia. Diabetes 57(2):444–450

    Article  PubMed  CAS  Google Scholar 

  35. Seo S, Ju S, Chung H, Lee D, Park S (2008) Acute effects of glucagon-like peptide-1 on hypothalamic neuropeptide and AMP activated kinase expression in fasted rats. Endocr J 55(5):867–874

    Article  PubMed  CAS  Google Scholar 

  36. Long YC, Zierath JR (2006) AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest 116(7):1776–1783

    Article  PubMed  CAS  Google Scholar 

  37. Silver IA, Erecinska M (1994) Extracellular glucose concentration in mammalian brain: continuous monitoring of changes during increased neuronal activity and upon limitation in oxygen supply in normo-, hypo-, and hyperglycemic animals. J Neurosci 14(8):5068–5076

    PubMed  CAS  Google Scholar 

  38. Lee K, Li B, Xi X, Suh Y, Martin RJ (2005) Role of neuronal energy status in the regulation of adenosine 5′-monophosphate-activated protein kinase, orexigenic neuropeptides expression, and feeding behavior. Endocrinology 146(1):3–10

    Article  PubMed  CAS  Google Scholar 

  39. Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D, Small CJ (2004) AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem 279(13):12005–12008

    Article  PubMed  CAS  Google Scholar 

  40. Manzoni C, Colombo L, Bigini P, Diana V, Cagnotto A, Messa M, Lupi M, Bonetto V, Pignataro M, Airoldi C, Sironi E, Williams A, Salmona M (2011) The molecular assembly of amyloid abeta controls its neurotoxicity and binding to cellular proteins. PLoS One 6(9):e24909

    Article  PubMed  CAS  Google Scholar 

  41. Scharf MT, Mackiewicz M, Naidoo N, O’Callaghan JP, Pack AI (2008) AMP-activated protein kinase phosphorylation in brain is dependent on method of killing and tissue preparation. J Neurochem 105(3):833–841

    Article  PubMed  CAS  Google Scholar 

  42. Hayes MR, Leichner TM, Zhao S, Lee GS, Chowansky A, Zimmer D, De Jonghe BC, Kanoski SE, Grill HJ, Bence KK (2011) Intracellular signals mediating the food intake-suppressive effects of hindbrain glucagon-like peptide-1 receptor activation. Cell Metab 13(3):320–330

    Article  PubMed  CAS  Google Scholar 

  43. Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG Jr, Schwartz MW (2001) Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature 413(6858):794–795

    Article  PubMed  CAS  Google Scholar 

  44. Niswender KD, Morrison CD, Clegg DJ, Olson R, Baskin DG, Myers MG Jr, Seeley RJ, Schwartz MW (2003) Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 52(2):227–231

    Article  PubMed  CAS  Google Scholar 

  45. Woods A, Vertommen D, Neumann D, Turk R, Bayliss J, Schlattner U, Wallimann T, Carling D, Rider MH (2003) Identification of phosphorylation sites in AMP-activated protein kinase (AMPK) for upstream AMPK kinases and study of their roles by site-directed mutagenesis. J Biol Chem 278(31):28434–28442

    Article  PubMed  CAS  Google Scholar 

  46. Garcia-Haro L, Garcia-Gimeno MA, Neumann D, Beullens M, Bollen M, Sanz P (2010) The PP1-R6 protein phosphatase holoenzyme is involved in the glucose-induced dephosphorylation and inactivation of AMP-activated protein kinase, a key regulator of insulin secretion, in MIN6 beta cells. Faseb J 24(12):5080–5091

    Article  PubMed  Google Scholar 

  47. McCrimmon RJ, Fan X, Cheng H, McNay E, Chan O, Shaw M, Ding Y, Zhu W, Sherwin RS (2006) Activation of AMP-activated protein kinase within the ventromedial hypothalamus amplifies counterregulatory hormone responses in rats with defective counterregulation. Diabetes 55(6):1755–1760

    Article  PubMed  CAS  Google Scholar 

  48. Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, Kozono H, Takamoto I, Okamoto S, Shiuchi T, Suzuki R, Satoh H, Tsuchida A, Moroi M, Sugi K, Noda T, Ebinuma H, Ueta Y, Kondo T, Araki E, Ezaki O, Nagai R, Tobe K, Terauchi Y, Ueki K, Minokoshi Y, Kadowaki T (2007) Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab 6(1):55–68

    Article  PubMed  CAS  Google Scholar 

  49. Kristensen P, Judge ME, Thim L, Ribel U, Christjansen KN, Wulff BS, Clausen JT, Jensen PB, Madsen OD, Vrang N, Larsen PJ, Hastrup S (1998) Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393(6680):72–76

    Article  PubMed  CAS  Google Scholar 

  50. Abbott CR, Rossi M, Wren AM, Murphy KG, Kennedy AR, Stanley SA, Zollner AN, Morgan DG, Morgan I, Ghatei MA, Small CJ, Bloom SR (2001) Evidence of an orexigenic role for cocaine- and amphetamine-regulated transcript after administration into discrete hypothalamic nuclei. Endocrinology 142(8):3457–3463

    Article  PubMed  CAS  Google Scholar 

  51. Ono H, Pocai A, Wang Y, Sakoda H, Asano T, Backer JM, Schwartz GJ, Rossetti L (2008) Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats. J Clin Invest 118(8):2959–2968

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Prof P. Mellon for the generous gift of the GT1-7 cell line. This work was supported by grants from MICINN (SAF2006-0475 and SAF2009-11297), Ayudas del Programa de Creación y Consolidación de Grupos de Investigación UCM-Banco Santander (GR58/08 and GR35/10A), Fundación de Investigación Médica Mutua Madrileña and IODURE project and CIBER de Diabetes y Enfermedades Metabólicas Asociadas, an initiative of ISCIII (Ministerio de Ciencia e Innovación).

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Elvira Alvarez.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 25 kb)

ESM 2

(DOC 32 kb)

ESM 3

(GIF 154 kb)

High Resolution Image (EPS 3957 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hurtado-Carneiro, V., Sanz, C., Roncero, I. et al. Glucagon-Like Peptide 1 (GLP-1) Can Reverse AMP-Activated Protein Kinase (AMPK) and S6 Kinase (P70S6K) Activities Induced by Fluctuations in Glucose Levels in Hypothalamic Areas Involved in Feeding Behaviour. Mol Neurobiol 45, 348–361 (2012). https://doi.org/10.1007/s12035-012-8239-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-012-8239-z

Keywords

Navigation